Olcorolimus

We have recently demonstrated a marked and selective augmentation of the bronchoconstrictor response to adenosine in actively sensitised Brown Norway (BN) rats challenged with ovalbumin (OA). The augmented response is mediated by 5-hydroxytryptamine (5-HT) released as a consequence of mast cell activation. We describe here the effects of budesonide, a clinically used glucocorticosteroid, IMM125, a hydroxyethyl derivative of D-serine-cyclosporine, MLD987, a close analogue of ascomycin and SAR943, a rapamycin derivative, on the hyperresponsiveness to adenosine induced in actively sensitised BN rats by exposure to allergen. Bronchoconstrictor responses to adenosine elicited 3 h following intratracheal (i.t.) instillation of OA, 0.3 mg kg(-1) were reduced dose-dependently by budesonide, IMM125, and MLD987, given i.t. 25 and 1 h prior to allergen challenge. In contrast, SAR943 had no effect on responses to adenosine. Responses to methacholine and 5-HT were minimally affected by these agents. Bronchoconstrictor responses to bradykinin were dose-dependently reduced by budesonide, but unaffected following IMM125, MLD987 or SAR943 pre-treatment. Challenge with OA at a dose of 0.3 mg kg(-1), induced increases in bronchoalveolar lavage (BAL) fluid, leukocyte numbers, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activities and protein concentration measured 24 h post challenge. Budesonide (1 mg kg(-1) given i.t. 25 and 1 h prior to OA challenge) induced reductions in the BAL fluid parameters of inflammation; IMM125 and MLD987, at a dose of 1 mg kg(-1) had no significant effect whereas SAR943 reduced lymphocyte numbers. Thus, budesonide, IMM125 and MLD987 block the hyperresponsiveness to adenosine induced by allergen challenge in sensitised rats. In the case of budesonide the effect is associated with a powerful, generalised anti-inflammatory effect although an effect directly on the mast cells is also likely. With IMM125 and MLD987, the effect is seen at doses that are not anti-inflammatory and may reflect direct suppression of mast cell activation by these agents.

No current therapy is considered to be satisfactory for severe asthma, and alternative approaches are still required for what is a major unmet medical need. In this study, we compared the effect of a rapamycin derivative, SAR 943, with budesonide, using a murine model of lung inflammation and remodeling. Allergen challenge of ovalbumin-sensitized BALB/c mice induced an increase in the levels of interleukin-5 and interleukin-4; numbers of eosinophil, neutrophil, and lymphocyte; cellular fibronectin; lung epithelial cell proliferation and mucus hypersecretory phenotype; as well as hyperreactivity to methacholine. Both SAR 943 and budesonide, when given intranasally 1 hour before and 24 hours after the aerosol challenge, inhibited all of these parameters with a similar potency (effective dose 50% of 1 mg/kg). In primary cultured smooth muscle cells from human airways, SAR 943 dose dependently inhibited epidermal growth factor-induced proliferation but did not affect the basal cell proliferation. Neither the basal nor stimulated proliferation of a human bronchial epithelial cell line (16HBE14o-) was affected by SAR 943. In conclusion, SAR 943 is as effective as budesonide in inhibiting both lung inflammation and remodeling in a murine model of asthma. Hence, this class of compound could offer beneficial effects in patients with severe asthma.